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Chromatin and transcriptomic profiling uncover dysregulation of the Tip60 HAT/HDAC2 epigenomic landscape in the neurodegenerative brain
Preprint   Open access

Chromatin and transcriptomic profiling uncover dysregulation of the Tip60 HAT/HDAC2 epigenomic landscape in the neurodegenerative brain

Mariah Beaver, Bhanu Karisetty, Haolin Zhang, Akanksha Bhatnagar, Ellen Armour, Visha Parmar, Reshma Brown, Merry Xiang and Felice Elefant
BioRxiv
27 Feb 2021
DOI: https://doi.org/10.1101/2021.02.27.433179
url
https://doi.org/10.1080/15592294.2021.1959742View
SubmittedOpen Access (License Unspecified),  Open

Abstract

Acetylation Alzheimer's disease Alzheimers disease Binding sites Chromatin Drosophila Epigenetics Gene disruption Genes Genomes HDAC2 protein Hippocampus Histone deacetylase Histones Insects Neurodegenerative diseases
ABSTRACT Disruption of histone acetylation mediated gene control is a critical step in Alzheimer’s Disease (AD), yet chromatin analysis of antagonistic histone acetyltransferases (HATs) and histone deacetylases (HDACs) causing these alterations remains uncharacterized. We report the first Tip60 HAT versus HDAC2 chromatin and transcriptional profiling study in Drosophila brains that model early human AD. We find Tip60 and HDAC2 predominantly recruited to identical neuronal genes. Moreover, AD brains exhibit robust genome-wide early alterations that include enhanced HDAC2 and reduced Tip60 binding and transcriptional dysregulation. Orthologous human genes to co-Tip60/HDAC2 Drosophila neural targets exhibit conserved disruption patterns in AD patient hippocampi. Notably, we discovered distinct transcription factor (TF) binding sites within Tip60/HDAC2 co-peaks in neuronal genes, implicating them in co-enzyme recruitment. Increased Tip60 protects against transcriptional dysregulation and enhanced HDAC2 enrichment genome-wide. We advocate Tip60 HAT/HDAC2 mediated epigenetic neuronal gene disruption as a genome-wide initial causal event in AD. Competing Interest Statement The authors have declared no competing interest.

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